P1073: MUTATIONAL LANDSCAPE AND CLINICAL OUTCOMES OF PATIENTS WITH MYELOID AND LYMPHOID NEOPLASMS WITH EOSINOPHILIA (MLN-EOS) AND ABNORMALITIES OF PDGFRA, PDGFRB, FGFR1, FLT3 AND JAK REARRANGEMENT
Authors: Y. Zhang, L. Nguyen, C. Lu, E. Wang, M. Lauw, S. Ball, N. Dong, L. Moscinski, O. Chan, S. Yun, D. Sallman, L. Sokol, B. Shah, J. Lancet, R. Komrokji, A. Kuykendall, E. Padron, L. Zhang
Journal: HemaSphere (2022)

Background: To recognize the growing list of recurrent genetically defined eosinophilia driven by constitutively active tyrosine kinase fusion genes, WHO created a provisional entity of myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) with rearrangement of PDGFRA, PDGFRB, FGFR1, or PCM1- JAK2. Aims: We aim to describe the mutational landscape and outcome with upfront targeted tyrosine kinase inhibitor (TKI) therapy in patients (pts) with MLN-Eo. Methods: We retrospectively reviewed clinical and molecular data on ptss with MLN-Eos with PDGFRA, PDGFRB, FGFR1, JAK2 or FLT3 rearrangement at Moffitt Cancer Center, Duke Cancer Center, and UCSF Comprehensive Cancer Center. The next generation sequencing of the bone marrow or peripheral blood was either done using our in-house targeted 54 gene myeloid panel or the commercially available panel, FoundationOneTM Heme Genomic profile. Pts were divided into two categories based on morphology at diagnosis: chronic and blastic phase disease. Median time to blastic phase and overall survival (mOS) were calculated using Kaplan Meier method and compared with log-rank test. Hazard ratio was calculated using the Cox proportional hazards (PH) model. Results: A total of 41 pts were included in the analysis. Thirteen patients had available comprehensive NGS results. 23 pts had PDGFRA fusion (21) or activating mutations (2); 4 had PDGFRB; 8 had FGFR1; 2 had JAK2, PCM-JAK2, and BCR-JAK2; 4 had FLT3, ETV6-FLT3 (3) and FLT3-TRIPP (1). Twelve (92%) patients had at least one other coexisting mutation. The mutations in at least two patients included TET2, RUNX1, TP53, and PTPN11 (Fig 1). Pathogenic PTPN11 mutation was present in all activating PDGFRA mutation but absent in other cases. Among 23 patients in chronic-phase disease 14 patients (61%) received the corresponding TKI to their fusion in the frontline setting. None transformed into blastic-phase disease. Six patients in the de novo blastic phase received the upfront TKI alone or combined with chemotherapy. All achieved complete remission (CR) and remained alive at a median follow-up of 44 months. In the OS analysis, upfront TKI use was associated with longer survival (HR 0.065; 95%CI, 0.008-0.50, p=0.008) in univariate analysis. The improved OS emained significant (HR 0.043, 95% CI 0.003-0.63, p=0.021) in multivariate analysis when adjusted for sex, age, hypereosinophilia in the blood, PDGFRA/B fusion status, complex cytogenetics at diagnosis, the blastic-phase at diagnosis, and alloHSCT. Image:Summary/Conclusion: Our study showed the high frequency of secondary somatic mutations in MLN-eos and described the mutational landscape similar to other myeloid malignancies. Targeted TKI therapies in the upfront setting are associated with excellent outcomes in patients with MLN-Eos. The elucidation of potential mechanisms needs further exploration.